Effectiveness of Drug Repurposing and Natural Products Against SARS-CoV-2: A Comprehensive Review

Abstract

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a betacoronavirus responsible for the COVID-19 pandemic, causing respiratory disorders, and even death in some individuals, if not appropriately treated in time. To face the pandemic, preventive measures have been taken against contagions and the application of vaccines to prevent severe disease and death cases. For the COVID-19 treatment, antiviral, antiparasitic, anticoagulant and other drugs have been reused due to limited specific medicaments for the disease. Drug repurposing is an emerging strategy with therapies that have already tested safe in humans. One promising alternative for systematic experimental screening of a vast pool of compounds is computational drug repurposing (in silico assay). Using these tools, new uses for approved drugs such as chloroquine, hydroxychloroquine, ivermectin, zidovudine, ribavirin, lamivudine, remdesivir, lopinavir and tenofovir/emtricitabine have been conducted, showing effectiveness in vitro and in silico against SARS-CoV-2 and some of these, also in clinical trials. Additionally, therapeutic options have been sought in natural products (terpenoids, alkaloids, saponins and phenolics) with promising in vitro and in silico results for use in COVID-19 disease. Among these, the most studied are resveratrol, quercetin, hesperidin, curcumin, myricetin and betulinic acid, which were proposed as SARS-CoV-2 inhibitors. Among the drugs reused to control the SARS-CoV2, better results have been observed for remdesivir in hospitalized patients and outpatients. Regarding natural products, resveratrol, curcumin, and quercetin have demonstrated in vitro antiviral activity against SARS-CoV-2 and in vivo, a nebulized formulation has demonstrated to alleviate the respiratory symptoms of COVID-19. This review shows the evidence of drug repurposing efficacy and the potential use of natural products as a treatment for COVID-19. For this, a search was carried out in PubMed, SciELO and ScienceDirect databases for articles about drugs approved or under study and natural compounds recognized for their antiviral activity against SARS-CoV-2.

Keywords: COVID-19; coronavirus; medicinal plants; pandemic.

Figure 1

Pathophysiology of COVID-19 disease and its systemic manifestations. Once SARS-CoV-2 enters the upper respiratory tract, it begins to replicate and spread there, in the hair cells. Infected people may remain asymptomatic but infectious or present with fever, cough, sputum, headache, or myalgia. At this time, innate immunity mediated by cytokines and interferons is responsible for controlling viral replication and limiting the severity of symptoms. If this does not happen, the disease worsens and the virus spreads to the lower respiratory tract where infects the alveolar type II cells and develops cough, sputum, dyspnea or ARDS, disseminated intravascular coagulation, and vascular permeability that affects the diffusion of oxygen, which contributes to a fatal disease. The factors that contribute to pulmonary and systemic disease are: 1. Direct cytotoxic effect: Persistent viral replication generates cell death and the release of DAMPs, PAMPs and cytokines causing endothelial inflammation. 2. Dysregulation of the renin-angiotensin-aldosterone system (RAAS): The RAAS is formed by different peptides, among which is the membrane ACE2 that cuts angiotensin I (Ang I into angiotensin 1–9 and Ang II into Ang 1–7 which have vasodilator, antiproliferative and antifibrotic functions. Decreased ACE2 enzymatic activity leads to vasoconstriction (hypertension) and thrombus formation. 3. Endothelium damage, inflammation and thrombus formation: Patients with COVID-19 may present excessive thrombin production (Endothelial cell damage activates the coagulation cascades) and inhibited fibrinolysis and complement activation, which causes microthrombi formation and vascular dysfunction. 4. Dysregulation of the immune response. Severe COVID-19 is characterized by T cell lymphopenia and hyperactivation of the immune system mainly neutrophils and macrophages that release an enormous amount of proinflammatory cytokines (cytokine storm) such as IL-1, IL-6, IL8, IL-10 and TNF, in addition, the formation of neutrophil extracellular traps (NETS) contributing to hyperinflammation. This figure was created in BioRender.

Figure 2

Molecular structure of chloroquine, hydroxychloroquine and ivermectin.

Figure 3

Molecular structure of zidovudine, lamivudine, lopinavir and Abacavir.

Figure 4

Molecular structure of ritonavir, lopinavir and remdesivir.

Figure 5

Molecular structure of emtricitabine, tenofovir and efavirenz.

Figure 6

Molecular structure of atorvastatin, ergocalciferol (D2) and cholecalciferol (D3).

Figure 7

Molecular structure of Isogranulatimide and resveratrol.

Figure 8

Molecular structure of neoechinulin A.

Figure 9

Molecular structure of punicalin and punicalagin.

Figure 10

Molecular structure of curcumin, hesperidin and quercetin.

Figure 11

Molecular structure of hinokiflavone and myricetin.

Figure 12

Molecular structure of betulinic acid.

Figure 13

Drugs with potential antiviral effects against SARS-CoV-2. The SARS-CoV-2 life cycle comprises eight main steps: 1. Virus entry by endocytosis or membrane fusion 2. Uncoating and release of viral RNA 3. Translation and cleavage of pp1a and pp1ab polyproteins (nonstructural proteins) 4. Assembly of the RTC 5. Replication or synthesis of full-length RNA copies 6. Translation or subgenomic RNA synthesis and translation of viral structural proteins (spike, membrane, envelope and nucleocapsid proteins) 7. Viral particles assembly in ERGIC 8. Release of the virus. HCQ could block the virus entry; the generation of viral proteins could be inhibited by the peptidomimetic lopinavir and efavirenz, which inhibit the posttranslational processing of viral polyproteins pp1a-pp1ab. The RNA replication and transcription can be affected by nucleoside analog zidovudine, lamivudine, Abacavir, remdesivir and tenofovir/emtricitabine, which prevent the proper functioning of RdRp and therefore inhibit negative-strand RNA and subgenomic RNA synthesis. Vitamin D and Atorvastatin modulate the immune response and protect against infection. This figure was created in BioRender.